Porphyrin compounds, particularly porphone derivatives obtained from hemoglobin, are known for their binding property with cancer tissue and photo-dynamic characteristics. Their use in cancer treatment is now being studied. However, production of porphyrin compounds requires animal blood which is limited in supply and needs extensive production steps. Animal blood, moreover, is not readily available as a commodity and phorphone derivatives, such as hematoporphyrine, which are said to be the active constituent of such derivatives are chemically unstable and it is extremely difficult to obtain them with high purity.
The present inventors have long been engaged in the study of chlorophyll related compounds and established a highly economical process for separating pheophorbide using naturally photo-synthesized organisms which are available in a stable and inexpensive supply and is described in Japanese Patent Application Laid-open No. 83-69884.
On the hypothesis that phorbines derived from pheophorbides may include compounds which demonstrate more potent physiological activities than porphines derived from blood, the present inventors continued their study and found for the first time that 9-desoxo-9-hydroxy-pheophorbide derivatives and their alkaline salts which are chemical reduction products of pheophorbide demonstrate highly potent physiological activities on cancer and photosensitivity (Japanese Patent Application No. 198934/83 and corresponding U.S. patent application Ser. No. 664,375).
Upon further studies, the present inventors found that other pheophorbide derivatives having various functional groups and their dimers (hereinafter referred to as the inventive compounds), and falling within the following general formula (A): ##STR3## wherein R.sub.1 represents --CH.dbd.CH.sub.2, --CH(OH)CH.sub.3, --CH(OCH.sub.2 CH.sub.2 OH)CH.sub.3 or --CH(OCOCH.sub.3)CH.sub.3
R.sub.2 represents --CH.sub.3, --CHO or --CH.sub.2 OH PA1 R.sub.3 represents .dbd.O, --OH or --OCOCH.sub.3 PA1 R.sub.4 represents --H, --COOCH.sub.3, --COOCH.sub.2 CH.sub.2 OH, --COOCH.sub.2 CH.sub.2 OCOCH.sub.3, or a --CONH-- containing residue of an amino acid and PA1 R.sub.5 represents --COOH, --COONa or --COOCH.sub.3 ;
exclusive of pheophorbide, 9-desoxy-9-hydroxy-pheophorbide, and pyropheophorbide, and the following general formula (B): ##STR4## wherein R.sub.1 through R.sub.5 are the same as general formula (A) and have excellent pharmacological properties, such as marked affinity to cancerous tissues, high photo-sensitivity and strong destructive effect upon irradiation on cancerous tissue that are superior to those observed with porphine compounds.
It has heretofore been known that porphone derivatives obtained from hemoglobin, i.e., hematoporphyrin and diacetyl hematoporphyrin, are likely to undergo conjugation with cancerous tissues and are photosensitive. Endo et al have recently found that 10-hydroxy-pheophorbide is carcinostatic (Japanese Patent Application Laid-open No. 185220/82). York et al reported on the bactericidal effect on ethylene-diamine hydrochloride of pheophorbide (Japanese Patent Application Laid-open No. 981/83). The latter application relates to an antibacterial agent comprising water soluble phorbine derived from pheophorbide by converting the same into its ethylenediamine hydrochloride salt.
As regards the instant dimers of general formula (B), processes for synthesizing chlorophyll dimers are disclosed in the literature (M. R. Wasielewski et al, C.A. 86, 68532f(1977), C.A. 88 148988r(1978) and S. G. Boxer et al, J.A.C.S., 1976, 5406), but these products are different. Moreover, the aim of these authors was to synthesize the chlorophyll dimers as a part of a study in elucidating the mechanism of photo-synthesis in order to obtain compounds having an UV absorption profile more similar to that of chlorophyll P-700. These references do not discuss the physiological activities of the compounds in question on cancerous tissues which are the main object of the present invention. It has so far been unknown that phorbines had such strong physiological activities.